1. Field of the Invention
The novel compositions of the present invention possess the advantageous pharmacological properties of the known free-base compound and in addition have unexpectedly high water-solubility, thus allowing preparation of useful dosage forms for intravenous administration.
2. Description of the Prior Art
The acridine derivative m-AMSA [4'9-(acridinylamino) methanesulfon-m-anisidide] has been reported by Cain, et al. in Europ. J. Cancer 10:539-549 (1974) to possess significant antitumor activity in animal tumor systems.
When an antitumor agent such as m-AMSA is employed for pharmaceutical use, it is recognized that solubility of the agent is often the controlling factor in determining route of administration and dosage forms. For instance, a water-soluble substance can be generally administered intravenously whereas a water-insoluble material is limited to other forms of parenteral administration such as intramuscular and subcutaneous. A therapeutic agent having water solubility also facilitates preparation of oral and non-intravenous parenteral dosage forms. Thus, it is decidedly advantageous if a therapeutic agent is water-soluble, particularly when one considers that the most direct route for achieving therapeutic blood levels of a drug is by intravenous administration.
The free-base form of m-AMSA has very limited solubility in water and thus cannot be used as a dosage form for intravenous administration. Attempts have been made to prepare acid addition salts to overcome this solubility problem, but the reported monohydrochloride and monomethanesulfonate salts also proved insufficiently water-soluble.
The use of various m-AMSA salts has been previously reported. U.S. Pat. No. 4,335,244 discloses the use of m-AMSA lactate hemiacetonate. U.S. Pat. No. 4,322,424 discloses the use of m-AMSA gluconate salts. European Patent No. 0 035 862 further discloses the use of the galacturonic, glucose-6-phosphate, gluconic, ascorbic, b-glycerophosphoric, glucuronic, glyceric, citric, acetic, propionic, gallic, isethionic, malonic, D,L-malic, succinic, d-tartaric, glutaric, mucic, phosphoric, salicylic, glycolic, benzoic, methanesulfonic,. gentisic, sulfuric, nitric and sulfamic salts of m-AMSA. However, while the salts disclosed are reported to be efficacious in varying degrees, they all have relatively low solubilities, i.e. less than 5-15 mg/ml of m-AMSA activity in the solvents employed, e.g. water, dimethylformamide, dimethylacetamide, methanol, anhydrous ethanol, isopropanol or combinations thereof.
The m-AMSA formulation presently in clinical use consists of two sterile liquids combined just prior to use. A solution of m-AMSA in anhydrous N,N-dimethylacetamide is contained in an ampule. A separate vial contains an aqueous L(+)-lactic acid solution for use as a diluent. When mixed, the resulting m-AMSA solution is administered by i.v. infusion.
While the present clinical formulation provides an intravenous dosage form, it suffers from several disadvantages. In addition to the obvious difficulties in preparing and administering the dosage form, it contains dimethylacetamide as a vehicle. Dimethylacetamide has been reported to show various toxic symptoms in animals and may thus prove to be unacceptable or undesirable as a pharmaceutical vehicle.
It is accordingly an object of the present invention to provide water-soluble, stable, therapeutically acceptable forms of m-AMSA which can be administered intravenously (as well as by other routes) and which do not contain or require dimethylacetamide as a pharmaceutical vehicle. This object as well as other features and advantages of the invention will be readily apparent to those skilled in the art from the disclosure set out below.